Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

Gerdts, Josiah; Sasaki, Yo; Vohra, Bhupinder P.S.; Marasa, Jayne; Milbrandt, Jeffrey

doi:10.1074/jbc.m111.250472

Cited by 64 publications

(70 citation statements)

References 25 publications

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“…With this setting, the retrograde propagation of the degenerative process towards the cell body of neurons upon axonal exposure to rotenone is delayed, presumably because it is buffered by the anterograde transport of undamaged material, thus deferring somatic degeneration 38,39 . The differences between somatic versus axonal protection conferred by the X protein or the PX3 peptide are likely owing to the fact that the molecular mechanisms involved in somatic and axonal degeneration differ significantly 21,40,41 . Axons are enriched in anti-apoptotic The PX3 peptide enters neurons and is targeted to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cellpermeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.

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Section: Discussionmentioning

confidence: 99%

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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“…Primary embryonic DRG cells were isolated from embryonic day (E) 13.5 mouse embryos as previously described (39). For rescue studies, DRGs were isolated from SARM1 −/− embryos at stage E13.5.…”

Section: Methodsmentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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121

125

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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“…In vitro, axons from Sarm1 Ϫ/Ϫ neurons are similarly preserved after transection. The sterile ␣ motif (SAM) and toll-interacting receptor (TIR) domains of Sarm1 are necessary to execute axon degeneration (Gerdts et al, 2013), whereas a fragment containing only the SAM-TIR domains is sufficient to induce cell death in sensory neurons and immortalized cell lines (Gerdts et al, 2013;Panneerselvam et al, 2013). In addition, loss of Sarm1 blocks neuronal cell death in models of oxygen-glucose deprivation and viral infection (Kim et al, 2007;Mukherjee et al, 2013).…”

Section: Axons In Sarm1mentioning

confidence: 99%

“…Recently, Sarm1 was identified as an essential component of the Wallerian degeneration program (Osterloh et al, 2012;Gerdts et al, 2013)…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

Summers

DiAntonio

Milbrandt

2014

Journal of Neuroscience

168

160

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Mitochondrial dysfunction is the underlying cause of many neurological disorders, including peripheral neuropathies. Mitochondria rely on a proton gradient to generate ATP and interfering with electron transport chain function can lead to the deleterious accumulation of reactive oxygen species (ROS). Notably, loss of mitochondrial potential precedes cellular demise in several programmed cell destruction pathways, including axons undergoing Wallerian degeneration. Here, we demonstrate that mitochondrial depolarization triggers axon degeneration and cell death in primary mouse sensory neurons. These degenerative events are not blocked by inhibitors of canonical programmed cell death pathways such as apoptosis, necroptosis, and parthanatos. Instead, the axodestructive factor Sarm1 is required for this axon degeneration and cell death. In the absence of Sarm1, the mitochondrial poison CCCP still induces depolarization of mitochondria, ATP depletion, calcium influx, and the accumulation of ROS, yet cell death and axon degeneration are blocked. The survival of these neurons despite the accumulation of ROS indicates that Sarm1 acts downstream of ROS generation. Indeed, loss of Sarm1 protects sensory neurons and their axons from prolonged exposure to ROS. Therefore, Sarm1 functions downstream of ROS to induce neuronal cell death and axon degeneration during oxidative stress. These findings highlight the central role for Sarm1 in a novel form of programmed cell destruction that we term sarmoptosis.

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Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

Cited by 64 publications

References 25 publications

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

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Image-based Screening Identifies Novel Roles for IκB Kinase and Glycogen Synthase Kinase 3 in Axonal Degeneration

Cited by 64 publications

References 25 publications

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation